1. Field of the Invention
The present invention relates to novel hydantoin derivatives, salts thereof, a process for the preparation thereof and a medicine comprising at least one of the derivatives or the salts as an effective ingredient to treat complications of diabetes and/or to prevent or cure circulatory diseases.
2. Related Arts
Hitherto, various studies have been made to find out an effective compound for curing diabetes, which compound can be formulated into a medicine for oral dosage. As a result, various drugs, each of which comprises as an effective ingredient, sulfonyl urea, mesooxalate, a guanidine derivative or the like have been developed and marketed for clinical use, but those are mere symptomatic treating agents to a hyperglycoplasmia due to the diabetes. It has been known there may be caused due to the diabetes specific chronic complications such as diabetic cataract, diabetic neuropathy, diabetic retinopathy and the like, but there is almost no effective agent for curing the complications and it may be said that no effective therapeutic system has been established.
Therefore, hitherto, various studies have also been made for developing an effective compound for curing such intractable diseases due to the diabetes but it is the fact that there has been is almost no success case. As one of studies for developing a compound for curing the complications of diabetes, there is a search on an anti- or inhibition substance to enzyme of aldose reductase, since the enzyme reduces in vivo of human being, and other animals, aldoses such as glucose and galactose into corresponding polyols such as sorbitol and galactitol and it has been known that the complications will appear when the formed sorbitol and galactitol are accumulated at crystalline lens, peripheral nerve, kidney or the like tissue or organ in patients with the diabetes or galactosemia ["Jap. J. Opthamol.", Vol. 20, page 399 (1976); Int. Congr. Ser. Excepta Med.", pages 403 and 594 (1977); and "Metabolism", Vol. 28, page 456 (1979)].
Some of the inventors and researchers in the assignee company have also studied and investigated substances showing the inhibition to aldose reductase to find out various hydantoin derivatives [Jap. Pat. Sho 61-200991(A) corresponding to U.S. Pat. No. 4,740,517 and EP 0193415(A2); and Jap. Pat. Nos. Sho 61-199924(A) and 61-126881(A) corresponding to U.S. Pat. No. 4,861,792 and EP 0264586(A1)].
Further, it has been known that there is a close relation between diabetes and circulatory diseases, since the arteriosclerosis is the complications of diabetes, which is caused with the highest frequency in occurrence and one of causes thereof lies in metabolic abnormality of lipids due to the diabetes. Moreover, a patient with a diabetic nephropathy has been often complicated with a circulatory disease of a hypertonia. In connection with this, such a report has been issued that a reduction in renal function of patients with diabetes can be delayed by carrying out a treatment for circulatory diseases and more particularly by dosing a hypotensor ["Br. Mrd. J.", Vol. 294, page 1443 (1987) and "N. Eng. J. Med.", Vol. 313, page 1617 (1985)].